Excess cardiovascular disease (CVD) with diabetes has been recognized for some time. Among diabetic individuals, CVD accounts for >50% of all deaths, and stroke accounts for an additional 15%.¹ Diabetic women are at particularly high risk of CVD; diabetes eliminates the well-described female advantage for coronary disease mortality.² This is alarming since the prevalence of type 2 diabetes is increasing, particularly in children.³

The Connection

In his 1988 Banting lecture, Reaven noted that resistance to insulin was common among patients with coronary artery disease.⁴ Some of these patients were frankly diabetic, but others had mildly impaired glucose tolerance and some had normal glucose tolerance. He also identified other CVD risk factors that were associated with resistance: hypertension, elevated triglycerides, and low high-density lipoprotein (HDL) cholesterol. He named this cluster ‘syndrome X.’ He attributed the co-existence of CVD risk factors and diabetes to elevated free fatty acids. The latter are increased with increasing visceral adiposity and lead to excessive triglyceride production by the liver, increased glucose output by the liver, and increased resistance to insulin in muscle cells. The rising insulin level will usually balance the resistance by increasing insulin production. In some, due to genetics, lipid or glucose toxicity, or ‘overproduction,’ insulin production fails to maintain strides with the resistance leading to various degrees of glucose intolerance. The UK Prospective Diabetes Study ⁵ of several thousand type 2 diabetic patients gave evidence that at the time of diagnosis of diabetes, half of beta cell function was gone. Thereafter, over the next 10–15 years, the function would continue to decline, leading to the failure of the oral antiglycemic medications and the need for insulin treatment. The implication, then, is early treatment of glucose intolerance and the associated CVD risk factors will lead to reduction in CVD events.

Diagnosing Diabetes

Diabetes is diagnosed only by the plasma glucose (see Table 1). If fasting glucose is greater than 125mg/dl on two consecutive occasions or if the second hour plasma glucose following a 75 glucose oral drink is greater than 199mg/dl on two consecutive occasions then the diagnosis of diabetes is secured.⁶ As mentioned above, glucose intolerance is a continuum—it is recognized that between ‘normal glucose’ and diabetes there exists a prediabetes condition. There are two forms of prediabetes: impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). IFG is diagnosed when the fasting plasma glucose is 100–125mg/dl on two consecutive periods and IGT is diagnosed when the second hour following a 75g oral glucose drink is 140–199mg/dl on two consecutive periods. It is important to properly diagnose these conditions. A person with prediabetes suffers an 11% chance/year of developing diabetes.⁷ Owing to the clustering of other CVD risk factors, such diagnosed patients have a greater risk of developing CVD. Owing to the genetic nature of glucose intolerance, family members of patients with prediabetes are also at increased risk for the same.

Reversing the Course

It is not only appropriate to delay or prevent diabetes in those diagnosed as prediabetic, but also to reduce the CVD risk factors associated with the prediabetic state.⁸ The Diabetes Prevention Program (DPP) ⁹ was a large, multicenter, placebo-controlled comparison of diet and increased activity, metformin, and troglitazone. The troglitazone treatment arm was discontinued during the first year of the study due to a death related to idiosyncratic hepatitis. Patients treated with a low-calorie, low-fat diet and 150 minutes of exercise a week to achieve a targeted weight loss of 7% of bodyweight were observed to have a reduced risk of developing diabetes of 58% compared with the control group. However, the subjects were recruited for the study only after rigorous screenings and successfully passing tests of compliance. In addition, the lifestyle modification consisted of individualized and group multiple sessions by nutritionist, exercise therapist, and other therapists. In summary, it was reassuring to see the effectiveness of such therapy, but the possibility of widespread clinical application of this approach is limited. The study was not designed to evaluate the CVD outcomes, but blood pressure in the diet/activity group was significantly less than that in the control group.